CYP2C9*2 (rs1799853) POLYMORPHISM AS A PHARMACOGENETIC PREDICTOR OF METHOTREXATE HEPATOTOXICITY IN RHEUMATOID ARTHRITIS PATIENTS OF AN UZBEK POPULATION
DOI:
https://doi.org/10.17605/Keywords:
Rheumatoid arthritis, CYP2C9*2, rs1799853, pharmacogenetics, methotrexate, hepatotoxicity, personalized dosing, Uzbek population.Abstract
Background: Methotrexate (MTX) remains the cornerstone of rheumatoid arthritis (RA) treatment, however its hepatotoxicity limits clinical application in up to 15–25% of patients. The CYP2C9*2 polymorphism (Arg144Cys, rs1799853) reduces enzyme activity by 30–50% and may modify MTX metabolism. The aim of this study was to investigate the association of CYP2C9*2 polymorphism with MTX-induced hepatotoxicity in RA patients of an Uzbek population of the Fergana Valley.
Methods: 100 patients with verified RA based on ACR/EULAR 2010 criteria and 73 ethnically-matched healthy controls were enrolled. Of 100 RA patients, 68 received methotrexate therapy at standard doses (15–25 mg/week) for at least 6 months. Hepatotoxicity was defined as elevation of ALT or AST above 2-fold the upper limit of normal (ULN = 40 U/L) on at least two consecutive measurements at least 4 weeks apart, in the absence of other causes. CYP2C9*2 genotyping was performed by real-time PCR with TaqMan probes. Multivariable logistic regression was applied to identify independent predictors of hepatotoxicity.
Results: CYP2C9*2 polymorphism showed no significant association with RA risk in the overall sample (OR=1.46; 95% CI: 0.83–2.57; p=0.195). Among 68 MTX-treated patients, 13 (19.1%) developed hepatotoxicity. Carriers of unfavorable CT+TT genotypes accounted for 61.5% of hepatotoxicity cases vs 25.5% in the no-hepatotoxicity group (OR=4.67; 95% CI: 1.42–15.3; p=0.012; AUC=0.71). Mean ALT levels were 28.4±3.8 U/L in CC homozygotes, 48.2±5.4 U/L in CT heterozygotes and 72.6±9.8 U/L in TT homozygotes (p<0.001 for trend). Multivariable logistic regression confirmed CYP2C9*2 CT+TT genotype as the strongest independent predictor of MTX hepatotoxicity (adjusted OR=4.86; 95% CI: 1.38–17.1; p=0.014) after adjustment for age, BMI, baseline liver enzymes and MTX dose.
References
1. Daly A.K., Rettie A.E., Fowler D.M., Miners J.O. Pharmacogenomics of CYP2C9: functional and clinical considerations. J. Pers. Med. 2017; 8(1): Article 1.
2. Fraenkel L., Bathon J.M., England B.R. et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021; 73(7): 924–939.
3. Kirchheiner J., Brockmöller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin. Pharmacol. Ther. 2005; 77(1): 1–16.
4. Macias Y., Gómez Tabales J., García-Martín E., Agúndez J.A.G. An update on the pharmacogenomics of NSAID metabolism and the risk of gastrointestinal bleeding. Expert Opin. Drug Metab. Toxicol. 2020; 16(4): 319–332.
5. Malik F., Ranganathan P. Methotrexate pharmacogenetics in rheumatoid arthritis: a status report. Pharmacogenomics. 2013; 14(3): 305–314.
6. Murav'ev Yu.V., Lebedeva V.V. Methotrexate and liver disease in rheumatic diseases. Nauchno-Prakticheskaya Revmatologiya. 2018; 56(4): 488–495.
7. Smolen J.S., Landewé R.B.M., Bergstra S.A. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann. Rheum. Dis. 2023; 82(1): 3–18.
8. Theken K.N., Lee C.R., Gong L. et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2C9 and nonsteroidal anti-inflammatory drugs. Clin. Pharmacol. Ther. 2020; 108(2): 191–200.
9. Wang J., Yu X., Zhang Y. et al. Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity in Chinese Han patients with rheumatoid arthritis. Pharmacogenomics. 2019; 20(15): 1109–1122.
10. Zhou Y., Ingelman-Sundberg M., Lauschke V.M. Worldwide distribution of cytochrome P450 alleles: a meta-analysis of population-scale sequencing projects. Clin. Pharmacol. Ther. 2017; 102(4): 688–700.
11. Zhou Y., Nevosadová L., Eliasson E., Lauschke V.M. Global distribution of functionally important CYP2C9 alleles and their inferred metabolic consequences. Hum. Genomics. 2023; 17: Article 15.
12. Zhu H., Deng F.Y., Mo X.B., Qiu Y.H., Lei S.F. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014; 15(4): 551–566.
